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Contribution of an SFK-Mediated Signaling Pathway in the Dorsal Hippocampus to Cocaine-Memory Reconsolidation in Rats

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Contribution of an SFK-Mediated Signaling Pathway in the Dorsal Hippocampus to Cocaine-Memory Reconsolidation in Rats Neuropsychopharmacology (2016) 41, 675–685 © 2016 American College of Neuropsychopharmacology. All rights reserved 0893-133X/16 www.neuropsychopharmacology.org Contribution of an SFK-Mediated Signaling Pathway in the Dorsal Hippocampus to Cocaine-Memory Reconsolidation in Rats 1 2 3 3 4 4 Audrey M Wells , Xiaohu Xie , Jessica A Higginbotham , Amy A Arguello , Kati L Healey , Megan Blanton and Rita A Fuchs*,3 1 2 Behavioral Genetics Laboratory, Department of Psychiatry, Harvard Medical School, McLean Hospital, Belmont, CA, USA; Department of 3 Chemistry, North Carolina State University, Raleigh, NC, USA; Department of Integrative Physiology and Neuroscience, Washington State University College of Veterinary Medicine, Pullman, WA, USA; 4Department of Psychology, University of North Carolina at Chapel Hill, Chapel Hill, NC, USA – – Environmentally induced relapse to cocaine seeking requires the retrieval of context response cocaine associative memories. These memories become labile when retrieved and must undergo reconsolidation into long-term memory storage to be maintained. Identification of the molecular underpinnings of cocaine-memory reconsolidation will likely facilitate the development of treatments that mitigate the impact of cocaine memories on relapse vulnerability. Here, we used the rat extinction-reinstatement procedure to test the hypothesis that the Src family of tyrosine kinases (SFK) in the dorsal hippocampus (DH) critically controls contextual cocaine-memory reconsolidation. To μ this end, we evaluated the effects of bilateral intra-DH microinfusions of the SFK inhibitor, PP2 (62.5 ng per 0.5 l per hemisphere), following re-exposure to a cocaine-associated (cocaine-memory reactivation) or an unpaired context (no memory reactivation) on subsequent drug context-induced instrumental cocaine-seeking behavior. We also assessed alterations in the phosphorylation state of SFK targets, including GluN2A and GluN2B N-methyl-D-aspartate (NMDA) and GluA2 α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor subunits at the putative time of memory restabilization and following PP2 treatment. Finally, we evaluated the effects of intra- DH PEAQX (2.5 μg per 0.5 μl per hemisphere), a GluN2A-subunit-selective NMDAR antagonist, following, or in the absence of, cocaine- memory reactivation on subsequent drug context-induced cocaine-seeking behavior. GluN2A phosphorylation increased in the DH during — — putative memory restabilization, and intra-DH PP2 treatment inhibited this effect. Furthermore, PP2 as well as PEAQX attenuated subsequent drug context-induced cocaine-seeking behavior, in a memory reactivation-dependent manner, relative to VEH. These findings suggest that hippocampal SFKs contribute to the long-term stability of cocaine-related memories that underlie contextual stimulus control over cocaine-seeking behavior. Neuropsychopharmacology (2016) 41, 675–685; doi:10.1038/npp.2015.217; published online 12 August 2015 INTRODUCTION cocaine-related memories can be therapeutically modified by interfering with memory reconsolidation (Tronson and Cocaine-associated environments evoke craving and Taylor, 2013). promote relapse, thereby impeding the successful treatment The dorsal hippocampus (DH) regulates the reconsolida- of cocaine addiction (Gawin and Kleber, 1986; Childress tion of contextual cocaine memories that direct instrumental et al, 1988). Implicit in this is the retrieval and utilization of – – cocaine-seeking behavior (Ramirez et al, 2009) through context response cocaine memories (Sorg, 2012; Tronson interactions with the basolateral amygdala (BLA; Wells et al, and Taylor, 2013). It is theorized that associative memories 2011). However, unlike the BLA, the DH contributes to are restabilized into long-term memory (LTM) storage via a cocaine-memory reconsolidation in a protein synthesis- protein synthesis-dependent memory reconsolidation independent manner that is poorly understood (Ramirez process following their retrieval and destabilization (Nader et al, 2009). Characterizing the intracellular signaling path- et al, 2000a). Therefore, it is possible that destabilized ways in the DH that control cocaine-memory reconsolida- tion fills a gap in our understanding and may advance the *Correspondence: Dr RA Fuchs, Department of Integrative Physiology development of novel therapeutics for relapse prevention. and Neuroscience, Washington State University College of Veterinary Medicine, PO Box 647620, Pullman, WA 99164-7620, USA, N-methyl-D-aspartate receptor (NMDAR) stimulation is Tel: +1 509 335 6164, Fax: +1 509 335 4650, necessary for drug-memory reconsolidation in several E-mail: [email protected] experimental procedures (Kelley et al, 2007; Sadler et al, Received 28 January 2015; revised 13 July 2015; accepted 15 July 2015; 2007; Brown et al, 2008; Milton et al, 2008a). NMDAR accepted article preview online 23 July 2015 function is regulated by the Src family of tyrosine kinases SFKs in cocaine-memory reconsolidation AM Wells et al 676 (SFKs; Salter and Kalia, 2004), which includes Src, Fyn, Lyn, Self-Administration and Extinction Training Yes, and Lck (Ohinishi et al, 2011). SFKs phosphorylate Rats were randomly assigned to one of two distinctly GluN2A (Nakazawa et al, 2001; Taniguchi et al, 2009) and different contexts (Context A or B, see Supplementary GluN2B NMDAR subunits (Nakazawa et al, 2001; Table S1) for self-administration training, which took place Prybylowski et al, 2005; Stramiello and Wagner, 2008) to during daily, 2 h sessions during the dark cycle. During these promote synaptic plasticity and memory (Purcell and Carew, 2003; Ohinishi et al, 2011). Specifically, SFK-mediated sessions, responses on a designated active lever produced cocaine infusions (cocaine hydrochloride; 0.15 mg per phosphorylation of GluN2A subunits is associated with 0.05 ml per infusion, intravenously; NIDA, Research Trian- synaptic strengthening and long-term potentiation (LTP; gle Park, NC) under an FR1 − 20 s time-out reinforcement Yang et al, 2012). Additionally, SFK activation in the dorsal schedule, as described previously (Fuchs et al, 2009). Presses striatum and DH is necessary for drug-induced behavioral on a second, inactive lever were recorded but had no phenomena, such as drug-primed ethanol-seeking (Wang scheduled consequences. Training continued until rats met et al, 2010) and context-elicited cocaine-seeking behaviors the acquisition criterion (ie, ⩾ 10 sessions with ⩾ 10 cocaine (Xie et al, 2013), respectively. However, the role of SFKs in infusions per session). drug-memory reconsolidation is unknown. Next, rats received seven daily 2 h extinction-training The present study tested the hypothesis that SFK-mediated signaling in the DH is necessary for the reconsolidation of sessions in the other context. Lever presses were recorded but had no programmed consequences. Rats in Experiments 1 contextual cocaine memories that promote instrumental and 3 were adapted to the intracranial microinfusion cocaine-seeking behavior. In Experiment 1, we evaluated (a) the effects of SFK inhibition in the DH during putative procedure after session 4. Rats in Experiment 2 were adapted to the same procedure after sessions 6 and 7 to minimize the memory reconsolidation on subsequent drug context-induced potential effects of infusion stress on protein expression (see cocaine-seeking behavior and (b) whether these effects Supplementary Methods). depended on explicit memory reactivation. In Experiment 2, we used quantitative western blotting to determine whether SFK inhibition in the DH during cocaine-memory reconsoli- Experiment 1a dation attenuates GluN2A NMDAR subunit phosphorylation. We also evaluated changes in alternate targets of SFKs: GluN2B In Experiment 1a, we evaluated whether intra-DH NMDA and GluA2 AMPA (α-amino-3-hydroxy-5-methyl-4- microinfusions of 4-Amino-3-(4-chlorophenyl)-1-(t-butyl)- isoxazolepropionic acid) receptor subunits (Hayashi et al, 1999; 1H-pyrazolo[3,4-d]pyrimidine, 4-Amino-5-(4-chlorophe- Hayashi and Huganir, 2004). Finally, in Experiment 3, we nyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2), an ATP- assessed the effects of a GluN2A-preferring NMDAR antago- competitive inhibitor of SFKs (Hanke et al, 1996), adminis- nist in the DH on cocaine-memory reconsolidation. tered during the putative time of cocaine-memory reconso- lidation would attenuate subsequent drug context-induced cocaine-seeking behavior. One day after the seventh MATERIALS AND METHODS extinction-training session, rats were re-exposed to the Animals previously cocaine-paired context for 15 min (ie, cocaine- memory reactivation; see experimental timeline in Figure 1a) Male Sprague–Dawley rats (N = 112; 275–300 g; Charles to trigger the destabilization and reconsolidation of context– River Laboratories, Wilmington, MA or Simonsen Labora- response–cocaine memories (Fuchs et al, 2009). The number tories, Gilroy, CA) were individually housed in a tempera- of extinction training sessions was uniform to control for ture- and humidity-controlled vivarium under a reversed memory age, a strong predictor of a memory’s sensitivity to light–dark cycle. Rats were fed 20–25 g of rat chow daily. destabilization (Suzuki et al, 2004; Inda et al, 2011), at the Water was available ad libitum. The housing and treatment time of memory reactivation. Lever pressing was recorded of rats followed the Guide for the Care and Use of Laboratory but was not reinforced during the memory reactivation Animals (National Research Council, 2011) and were session
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